The present invention is directed to a process for preparing a gonadotropin releasing hormone antagonist having an arylindole core.
The gonadotropin-releasing hormone (GnRH), also referred to as luteinizing hormone-releasing hormone (LHRH), is a decapeptide that plays a key role in human reproduction. The hormone is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland is primarily responsible for the regulation of gonadal steroid production in both sexes, whereas FSH regulates spermatogenesis in males and follicular development in females.
GnRH agonists and antagonists have proven effective in the treatment of certain conditions which require inhibition of LH/FSH release. In particular, GnRH-based therapies have proven effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and several gonadal steroid-dependent neoplasia, most notably cancers of the prostate, breast and ovary. GnRH agonists and antagonists have also been utilized in various assisted fertilization techniques and have been investigated as a potential contraceptive in both men and women. They have also shown possible utility in the treatment of pituitary gonadotrophe adenomas, sleep disorders such as sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, hirsutism, as an adjunct to growth hormone therapy in growth hormone deficient children, and in murine models of lupus.
Current GnRH antagonists are GnRH-like decapeptides which are generally administered intravenously or subcutaneously presumably because of negligible oral activity. These have amino acid substitutions usually at positions one, two, three, six and ten.
Non-peptide GnRH antagonists offer the possible advantage of oral administration. Non-peptide GnRH antagonists have been described in European Application 0 219 292 and in De, B. et al., J. Med. Chem., 32, 2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642 all to Takeda Chemical Industries, Ltd.
Substituted indoles known in the art include those described in the following patents and patent applications. Fisher et al. (U.S. Pat. No. 5,030,640) discloses alpha-heterocyclic ethanol aminoalkyl indoles which are potent xcex2-agonists.
Manning et al. (U.S. Pat. No. 4,544,663) is directed to indolamine derivatives which can be used as male anti-fertility agents.
Youngdale et al (WO 90/0572) discloses alpha-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents.
Boch et al. (French pat. No. 2,181,559) discloses indole derivatives with sedative, neuroleptic, analgesic, hypotensive, antiserotonin and adrenolytic activity.
Belgian patent 879381 discloses 3-aminoalkyl-1H-indole-5-thioamide and carboxamide derivatives as cardiovascular agents used to treat hypertension, Raynaud""s disease and migraine.
An object of the present invention is to develop an efficient synthetic route to prepare the class of GnRH antagonist compounds having regioselectivity and enantioselectivity, specifically the class of compound known as chiral tryptamines.
The present invention is directed a process for preparing a compound of Formula I, 
or its pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
p is: 1-4;
R1 is:
(1) hydrogen,
(2) (C1-C6)-alkyl, or
(3) aryl;
R2, R3, and R4 are independently:
(1) hydrogen,
(2) (C1-C6)-alkyl,
(3) (C2-C6)-alkenyl,
(4) CN,
(5) nitro,
(6) (C1-C3)-perfluoroalkyl,
(7) (C1-C3)-perfluoroalkoxy, or
(8) aryl;
R5 is:
(1) hydrogen,
(2) (C1-C6)-alkyl,
(3) aryl,
(4) (C1-C3)-perfluoroalkyl,
(5) CN,
(6) NO2, or
(7) halogen;
R6 and R7 are independently:
(1) hydrogen, or
(2) (C1-C6)-alkyl;
R8 is:
(1) (C1-C6)-alkyl; or
(2) aryl; and
R9 is:
(1) (C1-C6)-alkoxy, or
(2) NHR10R11, wherein R10 and R11 are independently:
(a) hydrogen,
(b) (C1-C6)-alkyl, or
(c) aryl,
xe2x80x83wherein R10 and R11 taken together form a monocyclic ring, bicyclic ring or bridged ring containing from 3 to 7 carbon atoms, and the ring may be optionally substituted by R2, R3, and R4; and
R12 is:
(1) (C1-C6)-alkyl,
(2) halo, wherein halo is F, Cl, Br or I,
(3) (C1-C4)-perfluoroalkyl,
(4) (CH2)nNMe3+ wherein n is 1 to 6, or
(5) aryl wherein aryl is optionally substituted with one, two, or three substituents selected from the group consisting of NO2, (C1-C6)-alkyl, and halo as defined above;
comprising the steps of:
(1) reacting a compound of formula (a), 
xe2x80x83with an aziridine compound of formula 
xe2x80x83in the presence of a Lewis-acid in an aprotic solvent to produce a compound of formula (b) 
xe2x80x83wherein R9a is (C1-C6)-alkoxy, hydrolyzing the compound of formula (b) in the presence of a base and a protic solvent to give an acid form of the compound of formula (b) wherein R9a is hydroxyl;
(2) reacting the acid form of the compound of formula (b) with an amine in an aprotic solvent to produce a compound of formula (c) 
(3) reacting the compound of formula (c) with amine, NHR10R11 in the presence of a base in an aprotic solvent to give an amide compound of formula (d), 
(4) reacting the compound of formula (d) with 
xe2x80x83in the presence of an acid in an aprotic solvent to give the compound of Formula I.
The present invention relates to a process for the synthesis of a gonadotropin releasing hormone antagonist in an efficient way, which involves preparation of key intermediates: 2-arylindole core; a chiral aziridine, in particular chiral nosyl aziridine; and an amine salt. The key step in the process is the coupling reaction of 2-arylindole and nosyl aziridine using boron trifluoride catalysis. The process of the present invention provides the compound of Formula I with unprecedented regioselectivity and enantioselectivity.
The present invention relates to a process for preparing a compound of Formula I, 
or its pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
p is: 1-4;
R1 is:
(1) hydrogen,
(2) (C1-C6)-alkyl, or
(3) aryl;
R2, R3, and R4 are independently:
(1) hydrogen,
(2) (C1-C6)-alkyl,
(3) (C2-C6)-alkenyl,
(4) CN,
(5) nitro,
(6) (C1-C3)-perfluoroalkyl,
(7) (C1-C3)-perfluoroalkoxy, or
(8) aryl;
R5 is:
(1) hydrogen,
(2) (C1-C6)-alkyl,
(3) aryl,
(4) (C1-C3)-perfluoroalkyl,
(5) CN,
(6) NO2, or
(7) halogen;
R6 and R7 are independently:
(1) hydrogen, or
(2) (C1-C6)-alkyl;
R8 is:
(1) (C1-C6)-alkyl; or
(2) aryl; and
R9 is:
(1) (C1-C6)-alkoxy, or
(2) NHR10R11, wherein R10 and R11 are independently:
(a) hydrogen,
(b) (C1-C6)-alkyl, or
(c) aryl,
xe2x80x83wherein R10 and R11 taken together form a monocyclic ring, bicyclic ring or bridged ring containing from 3 to 7 carbon atoms, and the ring may be optionally substituted by R2, R3, and R4; and
R12 is:
(1) (C1-C6)-alkyl,
(2) halo, wherein halo is F, Cl, Br or I,
(3) (C1-C4)-perfluoroalkyl,
(4) (CH2)nNMe3+ wherein n is 1 to 6, or
(5) aryl wherein aryl is optionally substituted with one, two, or three substituents selected from the group consisting of NO2, (C1-C6)-alkyl, and halo as defined above;
comprising the steps of:
(1) reacting a compound of formula (a), 
xe2x80x83with an aziridine compound of formula 
xe2x80x83in the presence of a Lewis-acid in an aprotic solvent to produce a compound of formula (b) 
xe2x80x83wherein R9a is (C1-C6)-alkoxy, hydrolyzing the compound of formula (b) in the presence of a base and a protic solvent to give an acid form of the compound of formula (b) wherein R9a is hydroxyl;
(2) reacting the acid form of the compound of formula (b) with an amine in an aprotic solvent to produce a compound of formula (c) 
(3) reacting the compound of formula (c) with amine, NHR10R11 in the presence of a base in an aprotic solvent to give an amide compound of formula (d), 
(4) reacting the compound of formula (d) with 
xe2x80x83in the presence of an acid in an aprotic solvent to give the compound of Formula I.
The process as recited above, wherein the aprotic solvent is selected from the group consisting of: isopropylacetate, ethylacetate, tetrahydrofuran, acetonitrile, toluene, pentane, hexane, benzene, dimethylacetamide, dimethylformamide, N-methylpyrrolidinone, diethyl ether, dichloromethane, chloroform, ethylacetate, and mixtures thereof.
The process as recited above, wherein the aziridine is a nosyl aziridine of formula 
The process as recited above, wherein a temperature range for the step (1) reaction is between about 0xc2x0 C. and about 60xc2x0 C.
The process as recited above, wherein the Lewis acid in step (1) is selected from the group consisting of group consisting of BF3xe2x80x94OEt2, BX3, SnX2, and SnX4 wherein X is halo. The preferred Lewis acid is BF3xe2x80x94OEt2.
The process as recited above, wherein the base in step (1) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide. The preferred base is sodium hydroxide.
The process as recited above, wherein the protic solvent is selected from the group consisting of (C1-C6)-alcohol, H2O or mixtures thereof. The preferred protic solvent is ethanol.
The process as recited above, wherein the amine in step (2) is NH3, NHR2 or NR3 wherein R is (C1-C6)-alkyl, which is selected from the group consisting of methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, sec-butylamine, n-tributylamine, tert-butylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, and triethylamine, tripropylamine, and tributylamine. The preferred amine is n-tributylamine.
The process as recited above, wherein the base in step (3) is selected from the group consisting of tert-butylamine, trimethylamine, triethylamine, tripropylamine, and tributylamine, tetramethyl piperidine, hexamethyldisilazane, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide and cesium hydroxide. The preferred base is triethylamine.
The process as recited above wherein the acid in step (4) is selected from the group consisting of triethylamine hydrochloride, phenol, (C1-C6)-alkanoic acid, (C1-C6)-alkanoic diacid, and (C1-C6)-alkanoic triacid each having a pKa less than 7. The preferred acid is acetic acid.
The process as recited above, wherein 
is present in amounts between about 4 equivalents and about 6 equivalents.
The process as recited above, wherein the step (3) reaction initially further comprises the steps of:
(i) breaking the salt compound of formula (c) wherein R9a is Oxe2x88x92NHR3+ using citric acid in an aprotic solvent to form a free acid of formula (c) wherein R9a is OH; and
(ii) reacting the free acid compound of formula (c) with a chlorinating agent in an aprotic solvent to form an acid chloride compound of formula (c) wherein R9a is Cl.
The process as recited above, wherein the chlorinating agent is SOCl2, oxalyl chloride, carbon tetrachloride, and triphenylphosphine dichloride. The preferred chlorinating agent is SOCl2.
The process as recited above, wherein the step (4) reaction initially further comprises deprotecting xe2x80x94S(O)2xe2x80x94R12 group of the compound of formula (d) using a mercaptan source and a base in a protic solvent to form the free amine compound of formula (d), 
The process as recited above, wherein the mercaptan source is selected from the group consisting of n-dodecanethiol, thiophenol, and mercaptoacetic acid. The preferred mercaptan source is n-dodecanethiol.
The process as recited above, wherein the base used for deprotecting xe2x80x94S(O)2xe2x80x94R12 group is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, calcium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. The preferred base is lithium hydroxide.
A preferred embodiment of the present invention is a process for preparing a compound of Formula Ixe2x80x2
or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R2, R3, and R4 are independently hydrogen or (C1-C6)-alkyl; comprising the steps of:
(1) reacting a compound of formula (a)xe2x80x2
xe2x80x83wherein R9a is OCH3, with a nosyl aziridine of formula 
xe2x80x83in the presence of a Lewis-acid in an aprotic solvent to produce a compound of formula (b)xe2x80x2
xe2x80x83hydrolyzing the compound of formula (b)xe2x80x2 in the presence of a base and a protic solvent to give an acid form of the compound of formula (b)xe2x80x2 wherein R9a is hydroxyl;
(2) reacting the acid form of the compound of formula (b)xe2x80x2 with n-tributylamine in an aprotic solvent to produce a compound of formula (c)xe2x80x2
(3) reacting the compound of formula (c)xe2x80x2 with isoquinuclidine in the presence of a base in an aprotic solvent to give an amide isoquinuclidinyl compound of formula (d)xe2x80x2
(4) deprotecting nosyl protected amine of formula (d)xe2x80x2 in the presence of n-dodecanethiol, a base, and a protic solvent to give a free amine of formula (d)xe2x80x3, 
(5) reacting the free amine of formula (d)xe2x80x3 with 
xe2x80x83in the presence of an acid in an aprotic solvent to give the compound of Formula Ixe2x80x2.
The process as recited above, wherein the aprotic solvent is selected from the group consisting of isopropylacetate, ethylacetate, tetrahydrofuran, acetonitrile, toluene, pentane, hexane, benzene, dimethylacetamide, dimethylformamide, N-methylpyrrolidinone, diethyl ether, dichloromethane, chloroform, ethylacetate, and mixtures thereof.
The process as recited above, wherein a temperature range for the step (1) reaction is between about 0xc2x0 C. and about 60xc2x0 C.
The process as recited above, wherein the Lewis acid in step (1) is selected from the group consisting of BF3xe2x80x94OEt2, BX3, SnX2, and SnX4 wherein X is halo. The preferred Lewis acid is BF3xe2x80x94OEt2.
The process as recited above, wherein the base in step (1) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide. The preferred base is sodium hydroxide.
The process as recited above, wherein the protic solvent is selected from the group consisting of (C1-C6)-alcohol, H2O or mixtures thereof. The preferred protic solvent is ethanol.
The process as recited above, wherein the base in step (3) is selected from the group consisting of tert-butylamine, trimethylamine, triethylamine, tripropylamine, and tributylamine, tetramethyl piperidine, hexamethyldisilazane, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide and cesium hydroxide. The preferred base is triethylamine.
The process as recited above, wherein the base in step (4) is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, calcium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. The preferred base is lithium hydroxide.
The process as recited above, wherein the acid in step (5) is acetic acid, which is present in amounts between about 2 equivalents and 4 equivalents.
The process as recited above, wherein 
is present in amounts between about 4 equivalents and about 6 equivalents.
The process as recited above, wherein the step (3) reaction initially further comprises the steps of:
(i) breaking the salt compound of formula (c) wherein R9a is Oxe2x88x92NHR3+ using citric acid in an aprotic solvent to form a free acid compound of formula (c) wherein R9a is OH; and
(ii) reacting the free acid compound of formula (c) with a chlorinating agent in an aprotic solvent to form an acid chloride compound of formula (c) wherein R9a is Cl.
The process as recited above, wherein the chlorinating agent is SOCl2, oxalyl chloride, carbon tetrachloride, and triphenylphosphine dichloride. The preferred chlorinating agent is SOCl2.
Another embodiment of the present invention is a process for preparing a compound of nosyl aziridine of formula 
comprising the steps of:
(A) reacting an amino alcohol of formula 
xe2x80x83with nosyl chloride in the presence of a base to form a dinosylated compound of formula 
xe2x80x83and
(B) cyclizing the dinosylated compound in the presence of a non-nucleophilic base in an aprotic solvent to produce the nosyl aziridine.
The process as recited above, wherein the base used for the preparation of nosy aziridine in Step (A) is selected from the group consisting of pyridine, trimethylamine, triethylamine, tripropylamine, tributylamine, quinoline, lutidine, 2,6-dibutylpyridine, tetramethyl piperidine, dimethylaminopyridine, and hexamethyldisilazane. The preferred base is pyridine.
The process as recited above, wherein the non-nucleophilic base used for the preparation of the nosyl aziridine in Step (B) is selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tripropylamine, tributylamine, quinoline, lutidine, 2,6-dibutylpyridine, tetramethyl piperidine, and dimethylaminopyridine. The preferred non-nucleophilic base is diisopropylethylamine.
Another aspect of present invention includes a process for preparing a compound of Formula II, 
or its pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
p is: 1-4;
R1 is:
(1) hydrogen,
(2) (C1-C6)-alkyl, or
(3) aryl;
R2, R3, and R4 are independently:
(1) hydrogen,
(2) (C1-C6)-alkyl,
(3) (C2-C6)-alkenyl,
(4) CN,
(5) nitro,
(6) (C1-C3)-perfluoroalkyl,
(7) (C1-C3)-perfluoroalkoxy, or
(8) aryl;
R5 is:
(1) hydrogen,
(2) (C1-C6)-alkyl,
(3) aryl,
(4) (C1-C3)-perfluoroalkyl,
(5) CN,
(6) NO2, or
(7) halogen;
R6 and R7 are independently:
(1) hydrogen, or
(2) (C1-C6)-alkyl;
R8 is:
(1) (C1-C6)-alkyl; or
(2) aryl;
R9 is:
(1) (C1-C6)-alkoxy, or
(2) NHR10R11, wherein R10 and R11 are independently:
(a) hydrogen,
(b) (C1-C6)-alkyl, or
(c) aryl,
xe2x80x83wherein R10 and R11 taken together form a monocyclic ring, bicyclic ring or bridged ring containing from 3 to 7 carbon atoms, and the ring may be optionally substituted by R2, R3, and R4; and
R12 is:
(1) (C1-C6)-alkyl,
(2) halo, wherein halo is F, Cl, Br or I,
(3) (C1-C4)-perfluoroalkyl,
(4) (CH2)nNMe3+ wherein n is 1 to 6, or
(5) aryl wherein aryl is optionally substituted with one, two, or three substituents selected from the group consisting of NO2, (C1-C6)-alkyl, and halo as defined above;
comprising the steps of:
reacting a compound of formula (a), 
xe2x80x83with an aziridine compound of formula 
xe2x80x83in the presence of a Lewis-acid in an aprotic solvent to produce a compound of formula II.
The process as recited above, wherein the aprotic solvent is selected from the group consisting of: isopropylacetate, ethylacetate, tetrahydrofuran, acetonitrile, toluene, pentane, hexane, benzene, dimethylacetamide, dimethylformamide, N-methylpyrrolidinone, diethyl ether, dichloromethane, chloroform, ethylacetate, and mixtures thereof
The process as recited above, wherein the aziridine is a nosyl aziridine of formula 
The process as recited above, wherein a temperature range is between about 0xc2x0 C. and about 60xc2x0 C.
The process as recited above, wherein the Lewis acid is selected from the group consisting of group consisting of BF3xe2x80x94OEt2, BX3, SnX2, and SnX4 wherein X is halo. The preferred Lewis acid is BF3xe2x80x94OEt2.
Yet another aspect of the present invention involves a process for preparing a compound of Formula III, 
or its pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
p is: 1-4;
R1 is:
(1) hydrogen,
(2) (C1-C6)-alkyl, or
(3) aryl;
R2, R3, and R4 are independently:
(1) hydrogen,
(2) (C1-C6)-alkyl,
(3) (C2-C6)-alkenyl,
(4) CN,
(5) nitro,
(6) (C1-C6)-perfluoroalkyl,
(7) (C1-C6)-perfluoroalkoxy, or
(8) aryl;
R5 is:
(1) hydrogen,
(2) (C1-C6)-alkyl,
(3) aryl,
(4) (C1-C3)-perfluoroalkyl,
(5) CN,
(6) NO2, or
(7) halogen;
R6 and R7 are independently:
(1) hydrogen, or
(2) (C1-C6)-alkyl;
R8 is:
(1) (C1-C6)-alkyl; or
(2) aryl;
R9 is:
(1) (C1-C6)-alkoxy, or
(2) NHR10R11, wherein R10 and R11 are independently:
(a) hydrogen,
(b) (C1-C6)-alkyl, or
(c) aryl,
xe2x80x83wherein R10 and R11 taken together form a monocyclic ring, bicyclic ring or bridged ring containing from 3 to 7 carbon atoms, and the ring may be optionally substituted by R2, R3, and R4; and
R12 is:
(1) (C1-C6)-alkyl,
(2) halo, wherein halo is F, Cl, Br or I,
(3) (C1-C4)-perfluoroalkyl,
(4) (CH2)nNMe3+wherein n is 1 to 6, or
(5) aryl wherein aryl is optionally substituted with one, two, or three substituents selected from the group consisting of NO2, (C1-C6)-alkyl, and halo as defined above;
comprising the steps of:
reacting the compound of formula, 
xe2x80x83with 
xe2x80x83in the presence of an acid in an aprotic solvent to give the compound of Formula III.
The process as recited above, wherein the aprotic solvent is selected from the group consisting of: isopropylacetate, ethylacetate, tetrahydrofuran, acetonitrile, toluene, pentane, hexane, benzene, dimethylacetamide, dimethylformamide, N-methylpyrrolidinone, diethyl ether, dichloromethane, chloroform, ethylacetate, and mixtures thereof.
The process as recited above, wherein the acid is selected from the group consisting of triethylamine hydrochloride, and phenol, (C1-C6)-alkanoic acid, (C1-C6)-alkanoic diacid, and (C1-C6)-alkanoic triacid each having a pKa less than 7. The preferred acid is acetic acid.
The process as recited above, wherein the acid is acetic acid, which is present in amounts between about 2 equivalents and 4 equivalents.
The process as recited above comprises the step of deprotecting xe2x80x94S(O)2xe2x80x94R12 group using a mercaptan source and a base in a protic solvent to form the free amine compound of formula, 
The process as recited above, wherein the mercaptan source is selected from the group consisting of n-dodecanethiol, thiophenol, and mercaptoacetic acid.
The process as recited above, wherein the base is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, calcium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
It is further understood that the substituents recited above would include the definitions recited below, and unless otherwise stated or indicated, the definitions shall apply throughout the specification and claims.
As used herein, the term xe2x80x9calkylxe2x80x9d includes those alkyls of a designated number of carbon atoms of either a straight, branched or cyclic configuration. Examples of xe2x80x9calkylxe2x80x9d includes but are not limited to: methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, and the like.
The term xe2x80x9calkenylxe2x80x9d includes hydrocarbon chains of a specified number of carbon atoms of ether a straight or branched configuration and at least one unsaturation, which may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, vinyl, allyl, 2-butenyl and the like.
The term xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and the like.
The term xe2x80x9carylxe2x80x9d is defined as phenyl or naphthyl, which may be optionally substituted with one, two or three substituents as set forth in the embodiment recited above.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refer to fluorine, chlorine, bromine and iodine.
The term xe2x80x9caminexe2x80x9d refers to primary, secondary, and tertiary amine. Examples of amine include, but are not limited to: methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, sec-butylamine, tert-butylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine tripropylamine, tributylamine, and the like.
The term xe2x80x9cacidxe2x80x9d as used herein includes triethylaminehydrochloride, phenol, (C1-C6)-alkanoic acid, (C1-C6)-alkanoic diacid, and (C1-C6)-alkanoic triacid each having a pKa less than 7.
Methods of preparing the compound of the present invention are illustrated in the following schemes and examples. All substituents are as defined above unless indicated otherwise. 
In Reaction Scheme A, the formation of nosyl aziridine, 2-methyl-1-(4-nitrophenylsulfonyl)aziridine (8) is obtained via a two-step, one-pot procedure in a single batch. Amino alcohol (7) is treated with excess nosyl chloride, ClS(O)2C6H4NO2 (herein after NosCl), in the presence of base, such as pyridine, to give a dinosylated intermediate of amino alcohol. Cyclization of the dinosylated amino alcohol is achieved in the presence of a non-nucleophilic base such as diisopropylethylamine (DIPEA) in ethylacetate to give the chiral aziridine product (8), which can be further crystallized from organic solvent such as isopropylaceate (IPAC). 
As shown in Reaction Scheme B, iodo aniline of type (4) reacts with aryl acetylene (3) in the presence of palladium catalyst such as PdCl2, phosphine (PPh3), a copper (I) halide such as copper iodide and diisopropylamine or triethylamine in an aprotic solvent such as toluene or tetrahydrofuran (THF) to give diarylacetylene compound (5). Cycloisomerization of diarylacetylene compound (5) in the presence of copper (I) iodide in an aprotic solvent such as dimethylformamide (DMF), toluene or a mixture thereof at a temperature of about 100xc2x0 C.xcx9c150xc2x0 C., preferably about 120xc2x0 C. to 140xc2x0 C. for about 4 to 10 hours to afford arylindole compound (6). 
In Reaction Scheme C, the nosyl aziridine (8) is coupled with arylindole (6) using stoichiometric boron trifluoride etherate (BF3OEt2) in an aprotic solvent such as toluene at a temperature of about 0xc2x0 C.xcx9c60xc2x0 C., preferably about 20xc2x0 C. to 30xc2x0 C., for about 7 to 24 hours to afford chiral tryptamine compound (9). Saponification of (9) using aqueous sodium hydroxide in a protic solvent such as ethanol gives a corresponding acid (9xe2x80x2) of the compound (9). The acid (9xe2x80x2) then reacts with a base such as n-tributylamine in isopropylacetate to afford the tributylamine salt (10) in high yield. 
As shown in Reaction Scheme D, salt breaking of (10) using citric acid in isopropylacetate (IPAC) is followed by acid chloride formation in the presence of chlorinating agent such as thionyl chloride (SOCl2) in an aprotic solvent, such as dimethylformamide (DMF). The crude acid chloride solution is then quenched directly into the isoquinuclidine tosylate in acetonitrile (ACN) and triethylamine (TEA) to afford the amide compound (11) in high yield. Deprotection of xe2x80x94SO2R12 group (e.g., nosyl group) from the amide (11) can be accomplished using a suitable mercaptan source such as dodecanethiol or thiophenol in the presence of a base such as lithium hydroxide in a protic solvent such as ethanol to yield the primary amine compound (12). The extracted amine compound (12) is then allowed to react with vinyl pyridine (about 4 to 6 equivalents, preferably about 5 equivalents) in the presence of acid catalyst such as acetic acid (about 2 to 4 equivalents, preferably about 3 equivalents) in an aprotic solvent such as toluene at a temperature about 60xc2x0 C. to 100xc2x0 C., preferably at about 80xc2x0 C., for about two to four hours to afford the final compound of chiral tryptamine (13). The final compound (13) can be further crystallized in organic solvent such as ethyl acetate.
The following examples illustrate the preparation of the compound of Formula I, and as such not to be considered as limiting the invention set forth in the claims appended hereto.